The earliest reports of high incidence of esophageal cancer (EC) in the northern parts of Iran date back to the early 1970s. A population-based cancer registry was established in 1969 as a joint effort between Tehran University and the International Agency for Research on Cancer (IARC). This registry confirmed the high incidence of EC in the eastern portion of the Caspian Sea littoral, in the area which is now known as Golestan Province. The highest incidence rates were reported from the semi-desert plain settled mainly by people of Turkmen ethnicity in Gonbad and Kalaleh counties. A series of studies were conducted in the region in the 1970s, but they were not conclusive in explaining the very high rates. Etiological hypotheses related to diet and life style can be best addressed in prospective cohort studies, in which measurement error can be reduced and recall bias is minimal. From 2002 to 2003, a pilot study of 1057 subjects was conducted by the Digestive Disease Research Center (DDRC) of Tehran University of Medical Sciences in collaboration with IARC and the US National Cancer Institute (NCI) to evaluate the logistical aspects of establishing a prospective study in Golestan. Subsequently, the Golestan Cohort Study (GCS) was launched in January 2004. The study protocol and the informed consent used for this study were approved by the ethical review committees of DDRC, IARC, and NCI. In June 2008, the accrual goal of 50 000 subjects was reached and enrollment was closed.